Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally neuronal, melanocytic, squamous, and enteroendocrine elements are found. Two histologic subtypes have clinical relevance: pure fetal histology throughout the tumor and foci of small cell undifferentiated cells.

Pure fetal histology hepatoblastoma

Analysis of patients with initially resected hepatoblastoma tumors (prior to receiving chemotherapy) has suggested that those patients with pure fetal histology tumors have a better prognosis than those having an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. In a study of patients with hepatoblastoma and pure fetal histology tumors, there was a 100% survival rate for patients who received four doses of single-agent doxorubicin.[1] This suggested that patients with pure fetal histology tumors might not need chemotherapy after complete resection of a stage I tumor.[2,3] In the Children's Oncology Group (COG) study COG-P9645, 16 patients with stage I pure fetal histology hepatoblastoma with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Their retrospective PRETEXT stages were stage I (n = 4), stage II (n = 6), and stage III (n = 2). Survival was 100% with no chemotherapy given.[4] All 16 patients entered on this study were alive with no evidence of disease at a median follow-up of 4.9 years (range, 9 months to 9.2 years).[4] Thus, complete resection of a pure fetal hepatoblastoma may preclude the need for chemotherapy.

Small cell undifferentiated hepatoblastoma

Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents a few percent of all hepatoblastomas. It tends to occur at a younger age (6–10 months) compared with other cases of hepatoblastoma [5,6] and is associated with AFP normal for age at presentation.[5,7]

Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[8] The chromosomal abnormalities reported for small cell undifferentiated hepatoblastoma are distinct from those occurring in other hepatoblastoma subtypes and are more similar to those observed in malignant rhabdoid tumors. These abnormalities include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1/INI1 gene.[5,9] Lack of detection of INI1 by immunohistochemistry is another characteristic shared by some small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors.[5] A third characteristic shared between small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors is the poor prognosis associated with each.[5,6,10] Patients with small cell undifferentiated hepatoblastoma whose tumors are unresectable have an especially poor prognosis.[5] Patients with stage I tumors appear to have increased risk of treatment failure when small cell elements are present.[11] For this reason, completely resected tumors composed of pure fetal histology or of mixed fetal and embryonal cells must have a thorough histologic examination as small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy.[11] Aggressive treatment for this histology is under investigation in the current COG study, COG-AHEP0731. Hepatoblastoma that would otherwise be considered very low or low risk is upgraded to intermediate risk if any small cell undifferentiated elements are found (refer to the Stage Information section of this summary for more information).

Hepatocellular Carcinoma

The cells of hepatocellular carcinoma are epithelial while hepatoblastoma has a less differentiated embryonal appearance. Hepatocellular carcinoma also differs from hepatoblastoma in that it often arises in a previously abnormal, cirrhotic liver. Both histologic types more commonly arise in the right lobe of the liver. Chronic hepatitis B is the leading cause of hepatocellular carcinoma in children in Asian and African countries; however, underlying liver disease can be identified in less than one-third of the children and adolescents with hepatocellular carcinoma in western countries.[12]

Fibrolamellar carcinoma

A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults. This histology is characterized by a fusion transcript created by deletion of a 400 kb section of chromosome 19, which was found in 15 of 15 tumors that were tested.[13] Fibrolamellar carcinoma is thought to be associated with an improved prognosis and is not associated with cirrhosis.[14-16] The improved outcome in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis, because the outcome in recent prospective studies, when compared stage for stage, is not different from other hepatocellular carcinomas.[12,17]; [18][Level of evidence: 3iiA] Fibrolamellar hepatocellular carcinoma has also been reported in infants.[19]

Transitional liver cell tumor

Transitional liver cell tumor is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy is poor, much like hepatocellular carcinoma.[20]

Undifferentiated Embryonal Sarcoma of the Liver

Undifferentiated embryonal sarcoma of the liver is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.[21] Distinctive features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.[22]

Infantile Choriocarcinoma of the Liver

These tumors are usually very friable and hemorrhagic and may present with bleeding into the tumor. The diagnosis can be made by imaging and findings of extremely high beta-human chorionic gonadotropin levels.

Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.[23]